Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS4581368 A
Publication typeGrant
Application numberUS 06/498,826
Publication dateApr 8, 1986
Filing dateMay 27, 1983
Priority dateMay 27, 1982
Fee statusPaid
Also published asDE3367092D1, EP0095906A1, EP0095906B1, US4596817, US4631289, US4757148
Publication number06498826, 498826, US 4581368 A, US 4581368A, US-A-4581368, US4581368 A, US4581368A
InventorsIsrar Ahmed, Gerald E. Adams, Ian J. Stratford
Original AssigneeNational Research Development Corporation
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Aziridino containing nitro imidazoles and pharmaceutical compositions
US 4581368 A
Abstract
A compound of formula I ##STR1## in which formula: R1 represents hydrogen or an alkyl group;
R2 -R5 represent hydrogen, alkyl aryl, aralkyl or alkaryl group; and
n is 1.
Images(5)
Previous page
Next page
Claims(9)
We claim:
1. A compound of formula I
in which formula:
R1 represents hydrogen or alkyl;
R2 -R5 represent hydrogen or alkyl; and
n is 1.
2. A compound according to claim 1 in which the nitro group is located at the 2-position in the imidazole ring.
3. A compound according to claim 1, in which at least one of R2 -R5 is an alkyl group.
4. A compound according to claim 1, in which at least two of R2 R3 R4 and R5 are C1 -C6 alkyl groups.
5. A compound according to claim 1, in which R1 represents hydrogen.
6. 1-(2-Nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol; 1-(2-Nitro-1-imidazolyl)-3-(2-isopropyl-1-aziridino)-2-propanol; 1-(2-Nitro-1-imidazolyl)-3-(2,3-dimethyl-1-aziridino)-2-propanol; or 1-(2-Nitro-1-imidazolyl)-3(2,2-dimethyl-1-aziridino)-2-propanol.
7. a pharmaceutical composition, comprising a radiation sensitizing effective amount or a chemopotentiating effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier or diluent therefor.
8. A formulation according to claim 7, in which the carrier or diluent is a saline drip.
9. A formulation according to claim 7, in unit dosage form.
Description

This invention relates to compounds useful in the treatment of cancer patients by radiotherapy or chemotherapy, to a process for the production of such compounds, to formulations for administration and to methods of treating such patients.

Accordingly, the present invention comprises a compound of formula I ##STR2## in which formula: R1 represents hydrogen or an alkyl (e.g. C1 -C6 alkyl) group;

R2 -R5 represent hydrogen, alkyl (e.g. C1 -C6 alkyl), aryl, aralkyl or alkaryl group; and

n is 1 or 2.

In compounds I, the nitro group is typically located at the 2-position on the imidazole ring and R1, when an alkyl group, e.g. a methyl group, is usually disposed at the 5-position. Generally, at least two of R2 -R5 are hydrogen and preferably at least one of R2 -R5 is an alkyl, e.g. a methyl, ethyl or isopropyl group or a benzyl group. Compounds wherein the group -NO2 is located at the 2-position, R1 represents hydrogen, n is 1 and R2, R3, R4 and R5 represent hydrogen or R2 and R3 represent methyl and R4 and R5 represent hydrogen or R2 and R4 represent methyl and R3 and R5 represent hydrogen are of particular interest.

The compounds are useful in increasing the sensitivity of tumour cells to radiation in radiotherapy and also in potentiating or enhancing damage to tumours by chemotherapeutic agents.

A compound I may be produced, in accordance with a further aspect of the present invention from compound II by treatment thereof with an aziridine of formula III preferably in a polar solvent such as an alcohol. ##STR3##

In a second process within the scope of the present invention for the production of the compound I, the compound of formula II is reacted with a compound of formula IIIA:

H2 NCR2 R3 CR4 R5 -X              IIIA

wherein X represents a halogen, typically chlorine or bromine, preferably in the presence of an acid acceptor e.g. an alkali metal hydroxide.

In a third process within the scope of the present invention for the production of the compound I, a compound IV ##STR4## wherein Y represents a halogen, typically bromine or chlorine, is reacted with an aziridine of formula III, preferably in the presence of an acid acceptor e.g. an alkali metal hydroxide.

In a fourth process within the scope of the present invention for the production of the compound I, a compound V ##STR5## is reacted with a compound of formula VI ##STR6## preferably under neutral or basic conditions.

In a fifth alternative process within the scope of the present invention for the production of the compound I, a compound of formula VII: ##STR7## wherein Z represents a halogen, typically bromine or chlorine, is cyclised by treatment with a base, typically an alkali metal hydroxide e.g. potassium or sodium hydroxide.

The above alternative processes are typically conducted in a polar solvent such as an alcohol.

When n is 2, compound I may be prepared by reaction of a compound of formula VIII with an aziridine of formula III suitably in a polar solvent such as methanol: ##STR8##

Intermediate compounds of formula VIII also form part of the present invention.

The compound I may be formulated in a manner appropriate to the treatment for which it is to be used by bringing it into association with a pharmaceutically compatible carrier or diluent. The compound may be included in a dosage form such as a tablet or capsule, for example a capsule comprising known formulation components such as one or more of those described in Example A of U.K. Patent Application 2003154A. The compound may also be formulated for intravenous administration e.g. in a saline drip solution.

When employed as a radiation sensitizing agent, in accordance with a further aspect of the present invention, the compound I is administered to a patient having a radiation sensitive cancer prior to irradiation of said cancer.

The compound I may, however, in yet a further aspect of the present invention be employed for chemopotentiation of a chemotherapeutic agent by administration of the compound I to a patient having a localised or metastatic cancer. Administration of the compound I is generally carried out prior to or simultaneously with administration of the chemotherapeutic agent, for example melphalan, cyclophosphamide, 5-fluorouracil or CCNU (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea).

The invention is illustrated by the following Examples:

EXAMPLE 1 1-(2-Nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol

A mixture of 1-(2,3-epoxypropyl)-2-nitroimidazole prepared by the method described by Beaman (Beaman A. G., Tautz W. and Duschinsky R., 1967; Studies in the Nitroimidazole Series, Antimicrobial Agents and Chemotherapy p. 520-530), (5.10 g, 0.03 mol) and aziridine (2.60 g., 0.06 mol) in methanol (70 ml) is heated under reflux for one hour. The reaction mixture is treated with decolourising charcoal, refluxed for 5 minutes and filtered. The solvent is removed under reduced pressure to a yellow residue, which is dissolved in a minimum quantity of ethanol and allowed to crystallize to give 1-(2-Nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol (3.57 g, 56%, m.p. 119-121 C.) as a pale yellow crystalline solid. Recrystallization causes the decomposition of the product.

EXAMPLE 2 AND 3

In the following Examples, WHT mice in which the MT tumour has been implanted subcutaneously are administered the compound of Example 1 intraperitoneally before treatment with radiation or with the chemotherapeutic agent melaphalan. The time before such treatment at which the drug is administered is such that maximum enhancement is effected. The results of treatment with radiation and the chemotherapeutic drug are set out respectively in Tables I and II together with comparison results using misonidazole (MISO) and the compound Ro-03-8799. The asterisks against the results from treatment with the latter compounds indicate that the tumours treated in these cases are intramuscular.

              TABLE I______________________________________           MISO  8799    Compound I______________________________________Example 2RadiosensitizationAdministered dose 3.8     3.8     3.8mmoles/kgEnhancement ratio 1.3     1.3     1.7Example 3Chemosensitization (melphalan)Administered dose 0.72    0.72    --mmoles/kgEnhancement ratio 1.7*    2.2*    --Administered dose --      0.72     0.08mmoles/kgEnhancement ratio --      1.9     3.0______________________________________
EXAMPLE 4 1-(2-Nitro-1-imidazolyl)-3-(2-methyl-1-aziridino)-2-propanol

In a manner analogous to that described in Example 1 there is obtained by reaction of 2-methyl aziridine with 1-(2,3-epoxypropyl)-2-nitroimidazole after crystallization from ethanol-ether, 1-(2-nitro-1-imidazolyl)-3-(2-methyl-1-aziridino)-2-propanol in the form of a pale yellow crystalline solid (3.06 g, 45%, m.p. 109-111 C.).

EXAMPLE 5 1-(2-Nitro-1-imidazolyl)-3-(2-ethyl-1-aziridino)-2-propanol

In a manner analogous to that described in Example 1 there is obtained by reaction of 2-ethylaziridine with 1-(2,3-epoxypropyl)-2-nitroimidazole after crystallization from ethanol-ether at -70 C., 1-(2-nitro-1-imidazolyl)-3-(2-ethyl-1-aziridino)-2-propanol in the form of a pale yellow crystalline solid which changes to a yellow thick oil at room temperature; yield 65%.

EXAMPLE 6 1-(2-Nitro-1-imidazolyl)-3-(2-benzyl-1-aziridino)-2-propanol

In a manner analogous to that described in Example 1, but using equimolar amounts of reagents, there is obtained from reaction of 2-benzyl aziridine with 1-(2,3-epoxypropyl)-2-nitroimidazole after column chromatography using silica gel as adsorbent, 1-(2-nitro-1-imidazolyl)-3-(2-benzyl-1-aziridino)-2-propanol in the form of a pale yellow gum, in 72% yield.

EXAMPLE 7 1-(2-Nitro-1-imidazolyl)-3-(2,2-dimethyl-1-aziridino)-2-propanol

In a manner analogous to that described in Example 1, there is obtained from reaction of 2,2-dimethyl aziridine with 1-(2,3-epoxypropyl)-2-nitroimidazole after crystallization from ethanolether, 1-(2-nitro-1-imidazolyl)-3-(2,2-dimethyl-1-aziridino)-2-propanol in the form of a pale yellow crystalline solid of melting point 101-103 C.; yield 78%.

EXAMPLE 8 1-(2-Nitro-1-imidazolyl)-3-(2-phenyl-1-aziridino)-2-propanol

The compound is preparable by reaction of 1-(2,3-epoxypropyl)-2-nitroimidazole with 2-phenylaziridine (K. Ichimura and M. Ohta, Bull. Chem. Soc. Japan, 43(5) 1443-50 (1970)) in methanol, following the method described in Example 1.

EXAMPLE 9 1-(2-Nitro-1-imidazolyl)-3-(2-isopropyl-1-aziridino)-2-propanol

The compound is preparable by reaction of 1-(2,3-epoxypropyl-2-nitroimidazole with 2-isopropylaziridine (K. Ichimura, Bull. Chem. Soc. Japan 43 1443-50 (1970)) in methanol following the method described in Example 1.

EXAMPLE 10 1-(2-Nitro-1-imidazolyl)-4-(1-aziridino) or substituted aziridino)-2,3-butane-diol. (I,R1 ═H, n=2, R2 -R5 ═H or alkyl, aryl, aralkyl or alkaryl) (a) 1-(2-nitroimidazolyl)-2-hydroxy-3,4-epoxy butane

3-(2-Nitroimidazolyl)-2-hydroxy-1-butene (11.83 gms, m.p. 90-92 C., prepared by refluxing a mixture of azomycin, 1,3-butadiene monoxide and anhydrous potassium carbonate in ethanol for 5 hours) is stirred overnight in dichloroethane with m-chloroperbenzoic acid in the presence of 3-tert-butyl-4-hydroxy-5-methylphenyl sulfide and after stirring the reaction mixture is refluxed for 1 hour. The mixture is washed with saturated sodium carbonate solution and the aqueous phase was extracted with chloroform. The combined dichloroethane and chloroform extracts are concentrated to a small volume and the product is purified by column chromatography, in which silica gel is the stationary phase and a mixture of chloroform (90%) and ethanol (10%) the eluent. The product is crystallised from ethanol as a pale yellow solid of m.p. 134-136 C. Yield 33%.

(b) The compound from (a) is reacted with an aziridine of formula III in methanol to yield the required compound of formula I.

EXAMPLE 11 1-(2-methyl-5-nitro-1-imidazolyl)-3-(1-aziridino or substituted aziridino)-2-propanol. (I,R1 ═CH3, n=1,R2 -R5 ═H alkyl, aryl, aralkyl or alkaryl)

1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole (M. Hoffer and E. Grunberg, J. Med. Chem. 17, 1019 (1974)) is reacted with an aziridine of formula III in methanol to yield the required compound of formula I.

EXAMPLE 12 1-(2-methyl-4-nitro-1-imidazolyl)-3-(1-aziridino or substituted aziridino)-2-propanol. (I,R1 ═CH3, n=1,R2 -R5 ═H alkyl, aryl, aralkyl or alkaryl)

The procedure of Example 11 is repeated using 1-(2,3-epoxypropyl)-2-methyl-4-nitroimidazole (J. Suwinski, E. Suwinska, J. Watras (1974) and M. Widel, Acta Pol. Pharm., 15(5), 529 (1975)) to yield the required compound of formula I.

EXAMPLES 13 AND 14 1-(2-Nitro-1-imidazolyl)-3-(2,3-dimethyl-1-aziridino)-2-propanol (meso and dl forms)

A mixture of meso and dl forms of 2,3-dimethylaziridine, prepared by the method of Dickey described in J. Amer. Chem Soc. Vol. 74, p 944 (1952), is reacted with 1-(2,3-epoxypropyl)-2-nitroimidazole in a manner analogous to that described in Example 1, to yield a mixture of the meso and dl forms of 1-(2-nitro-1-imidazolyl)-3-(2,3-dimethyl-1-aziridino)-2-propanol (isomers reflect the presence of two chiral centres in the aziridinyl moiety). The meso and dl forms are separated by column chromatography in which silica gel is the stationary phase and a mixture of diethyl ether (95%) and ethanol (5%) the eluant. The meso form has m.p. 84-5 and the dl form is isolated as a waxy solid.

Sensitisation and toxicity data for compounds described in the above Examples are set out in Table II.

                                  TABLE II__________________________________________________________________________Sensitisation and toxicity data on Compounds described in the Examples                                          Therapeutic ratiodExample Position of                            relative to CompoundnumberR1   NO2 group         n R2                 R3                    R4                       R5                         C1.6 /mol dm-3.spsp.a                                 LD50 /mmol/kgb                                          of Example__________________________________________________________________________                                          11    H  2     1 H     H  H  H 1.0  10-4                                 0.61c                                          14    H  2     1 Me    H  H  H 8  10-5                                 <0.58    <1.26    H  2     1 PhCH2                 H  H  H5    H  2     1 Et    H  H  H 1.3  10-4                                 0.58     0.737    H  2     1 Me    Me H  H 8  10-5                                 1.25     2.568    H  2     1 Ph    H  H  H 3  10-413   H  2     1 Me(meso)                 H  Me H 8  10-5                                 ≧ 1.25                                          2.5614   H  2     1 Me(dl)                 H  Me H 8  10-510   H  2     2 H     H  H  H 1.3  10-4                                 0.41     0.5211   2-Me   5     1 H     H  H  H 3  10-4                                 0.80     0.4412   2-Me   4     1 H     H  H  H9    H  2     1            ##STR9##                 H  H  H 1.3  10-4                                 ≧1.18                                          1.49__________________________________________________________________________ a Concentration required to achieve an enhancement ratio of 1.6 in irradiated hypoxic V79 mammalian cells. b Drugs administered i.p. to ♀ WHT mice. ##STR10## ##STR11##
Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US4241060 *Aug 3, 1978Dec 23, 1980Hoffmann-La Roche Inc.Nitroimidazoles and compositions thereof
US4282232 *Apr 26, 1979Aug 4, 1981Research CorporationNitroimidazole radiosensitizers for hypoxic tumor cells and compositions thereof
EP0000928A1 *Aug 17, 1978Mar 7, 1979F. HOFFMANN-LA ROCHE &amp; CO. AktiengesellschaftNitroimidazoles and pharmaceutical compositions containing them as well as their preparation
GB2003154A * Title not available
Non-Patent Citations
Reference
1 *Adams et al., British Journal of Cancer (1984), vol. 49, 571 577.
2Adams et al., British Journal of Cancer (1984), vol. 49, 571-577.
3 *Smithen et al., Chemical Abstracts, vol. 95, (1981), No. 17999s.
4 *Stratford, Int. J. Radiation Biol. Phys., vol. 8, 391 392, (1982).
5Stratford, Int. J. Radiation Biol. Phys., vol. 8, 391-392, (1982).
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4797397 *Jul 31, 1987Jan 10, 1989Warner-Lambert CompanyX-rays therapy of tumors
US4954515 *Nov 25, 1988Sep 4, 1990Warner-Lambert CompanyHaloalkylaminomethyl-2-nitro-1H-imidazoles
US5036089 *Jun 4, 1990Jul 30, 1991Warner-Lambert CompanyAntitumor agents
US5036096 *Jun 4, 1990Jul 30, 1991Warner-Lambert CompanyAziridino derivatives of nitroimidazoles and pharmaceutical compositions of selected derivatives
US5073639 *Jun 4, 1990Dec 17, 1991Warner-Lambert CompanyProcess for the synthesis of novel and known nitroimidazoles which are useful as sensitizing agents
US5177075 *Sep 11, 1991Jan 5, 1993Warner-Lambert CompanySubstituted dihydroisoquinolinones and related compounds as potentiators of the lethal effects of radiation and certain chemotherapeutic agents; selected compounds, analogs and process
US5481000 *Dec 19, 1994Jan 2, 1996Warner-Lambert CompanyProcess for preparing chiral [[(2-bromoethyl)-amino]methyl]-2-nitro-1H-imidazol-1-ethanol and related compounds
US5521203 *Dec 9, 1994May 28, 1996British Technology Group LimitedNitro-substituted aromatic or hetero-aromatic compounds for use in cancer treatment
US5543527 *May 18, 1995Aug 6, 1996British Technoloyg Group LimitedProcess for preparing chiral [[(2-bromoethyl)-amino]methyl]-nitro-1H-imidazol-1-ethanol and related compounds
US5659048 *May 23, 1995Aug 19, 1997British Technology Group LimitedChiral [[(2-bromoethyl)-amino]methyl]-2-nitro-1H-imidazol-1-ethanol and related compounds
US6403359Sep 25, 1998Jun 11, 2002V. I. TECHNOLOGIES, Inc.Deactivation electrophiles
US6617100Mar 1, 1999Sep 9, 2003V.I. Technologies, Inc.Solid phase quenching systems
US6720136Jun 11, 2002Apr 13, 2004V. I Technologies, Inc.Solid phase quenching systems
US20110118191 *Nov 15, 2010May 19, 2011Reid Paul FCrotoxin Administration for Cancer Treatment and Pain Relief
WO2000018412A1 *Sep 22, 1999Apr 6, 2000Pentose Pharmaceuticals IncSolid phase quenching systems
Classifications
U.S. Classification514/397, 548/327.5, 548/314.7, 548/330.1, 548/311.1, 548/328.5
International ClassificationA61N5/10, C07D405/06, C07D233/00, A61K31/415, A61P35/00, C07D203/00, C07D303/00, A61N5/00, C07D403/06, A61K31/41, A61K31/396, C07D233/91
Cooperative ClassificationC07D405/06, C07D233/91, C07D403/06
European ClassificationC07D233/91, C07D405/06, C07D403/06
Legal Events
DateCodeEventDescription
Sep 22, 1997FPAYFee payment
Year of fee payment: 12
Sep 27, 1993FPAYFee payment
Year of fee payment: 8
Aug 11, 1992ASAssignment
Owner name: BRITISH TECHNOLOGY GROUP LIMITED, ENGLAND
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:NATIONAL RESEARCH DEVELOPMENT CORPORATION;REEL/FRAME:006243/0136
Effective date: 19920709
Sep 18, 1989FPAYFee payment
Year of fee payment: 4
Dec 27, 1985ASAssignment
Owner name: NATIONAL RESEARCH DEVELOPMENT CORPORATION, 101 NEW
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:AHMED, ISRAR;ADAMS, GERALD E.;STRATFORD, IAN J.;REEL/FRAME:004491/0182
Effective date: 19840613